APPLICANTS ABSTRACT: In the past two years a swine model was developed to evaluate the effects of chronic opiate abuse on the immune system and resistance to disease. Now we propose to investigate the molecular and cellular basis for specific immunosuppressive effects of chronic morphine treatment in pigs. We will test the hypothesis that under conditions of chronic administration, (1) Opiate drugs suppress specific local immune functions by rendering lymphocytes or macrophages unresponsive to antigenic stimulation, and (2) Mechanisms of action involve modulation of cytokine gene expression especially the down regulation of interleukin-1. Previous studies have established that morphine- treated pigs exhibit a marked deficit in the delayed type hypersensitivity response, whereas humoral immune responses to various viral and bacterial antigens are largely intact. Interestingly, the ability to produce interleukin-1 is suppressed in macrophages from morphine-treated pigs. Since its plays a key role in the modulation of cellular immune responses and exerts stress- related effects on the brain, an opiate-mediated suppression of IL-1 expression may contribute to the role of opiate drugs as a cofactor for HIV infection and AIDS. In Part I we will focus on understanding the cellular and molecular features of the DTH response which are affected by opiates, namely morphine. We will study in vivo effects of morphine on cellular infiltrates at the site of a DTH lesion and their secretion of inflammatory and immunoregulatory cytokines. These data should be helpful in understanding in vivo the effects of opiate drugs on cellular interactions and immune regulation at the local level. In Part II we will develop and evaluate an in vitro model to study the molecular basis of opiate-mediated suppression of cytokine expression, especially IL-1. We postulate that a failure of IL-1 production by macrophages in the inflammatory site results in a failure of DTH- responsive T cells to become activated or a failure to recruit additional macrophages and neutrophils. Thus abrogating the inflammatory response. The in vitro model will permit direct examination of opiate effects, both direct and indirect, on cytokine expression in defined cell populations. Parts I and II serve as complementary approaches for improving our understanding of the effects of opiate drug dependence on health maintenance, with particular reference to AIDS, in the human population.